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Meza R.C.,University of Santiago de Chile | Ortiz F.C.,University of Santiago de Chile | Bravo E.,University of Santiago de Chile | Iturriaga-Vasquez P.,University of Chile | And 3 more authors.
Neurochemistry International | Year: 2012

The carotid bodies (CBs) are chemosensory organs that respond to hypoxemia with transmitter neurosecretion, leading to a respiratory reflex response. It has been proposed that acetylcholine is a key regulator of transmitter release through activation of presynaptic nicotinic acetylcholine receptors (nAChRs). In the present work, we studied the identity of such nAChRs and their contribution to catecholamine release from CBs. Neonatal rat CBs were placed in a recording chamber for electrochemical recordings or disassociated for voltage-clamp studies on isolated cells. Fast nicotine superfusion increases catecholamine release from intact CBs. This response was diminished reversibly by the non-selective nAChR blocker hexamethonium, by the selective α7 blocker α-bungarotoxin and by the α4-containing nAChR blocker erysodine. In isolated CB cells the nAChR agonists nicotine, acetylcholine and cytisine all evoke inward currents with similar potencies. The nicotine-evoked current was fully blocked by mecamylamine and partially inhibited by α-bungarotoxin or erysodine. However, the combination of both α-bungarotoxin an erysodine failed to suppress this response. Immunodetection studies confirm the presence of α7 and α4 subunits in isolated dopaminergic CB cells. Our results show that activation of α7 and/or α4-containing nAChR subtypes have the ability to regulate catecholamine release from intact CB due to activation of fast inward currents expressed in chemoreceptor cells. Therefore, our results suggest that both nAChR subtypes contribute to the cholinergic nicotinic regulation of catecholamine signaling in the carotid body system. © 2011 Elsevier Ltd. All rights reserved.

Galdamez A.,University of Chile | Garcia-Beltran O.,Andres Bello University | Cassels B.K.,University of Chile | Cassels B.K.,Millennium Institute for Cell Dynamics and Biotechnology
Journal of the Chilean Chemical Society | Year: 2011

The crystal structure of ethyl 7-hydroxy-2-oxo-2H-chromene-3-carboxylate monohydrate (1), C12H10O5.H2O, was established by X-ray crystallographic analysis. The molecule of the title compound is essentially planar except for the carboxylate substituent group. The crystal packing supramolecular array arises from hydrogen bonds and intermolecular C-H⋯O=C contacts of the organic molecules and solvent water molecules, with graph-set descriptor)R2 4(8), R 2 1(6), R4 4(20)and5 (C) motifs. The water molecules are involved as donors and acceptors. The hydrogen bond and intermolecular interaction network is reinforced by stacking of the sheet through π-π interactions.

Castro-Castillo V.,Metropolitan University of Educational Sciences | Castro-Castillo V.,University of Chile | Rebolledo-Fuentes M.,University of Chile | Theoduloz C.,University of Talca | And 2 more authors.
Journal of Natural Products | Year: 2010

Lakshminine (6-amino-1-aza-5-methoxy-7H-dibenzo[de,h]quinolin-7-one, 1) is a recent addition to the small family of oxoisoaporphine alkaloids and a member of an even smaller set bearing an amino group at C-6. This rare natural product has now been synthesized in order to have sufficient amounts for biological testing. Lakshminine, its 4-amino isomer (2), their 6- and 4-nitro precursors (8 and 10, respectively), the intermediate 5-methoxy-7H-dibenzo[de,h]quinolin-7- one (6), and the unsubstituted skeleton (11) were tested against normal human fibroblasts and three human solid tumor cell lines. Only compound 10 showed marginal antiproliferative activity. © 2010 The American Chemical Society and American Society of Pharmacognosy.

Encina G.,University of Chile | Encina G.,Millennium Institute for Cell Dynamics and Biotechnology | Ezquer F.,University for Development | Conget P.,University for Development | And 3 more authors.
Biological Research | Year: 2011

Transgenic mice carrying the human insulin gene driven by the K-cell glucose-dependent insulinotropic peptide (GIP) promoter secrete insulin and display normal glucose tolerance tests after their pancreatic β-cells have been destroyed. Establishing the existence of other types of cells that can process and secrete transgenic insulin would help the development of new gene therapy strategies to treat patients with diabetes mellitus. It is noted that in addition to GIP secreting K-cells, the glucagon-like peptide 1 (GLP-1) generating L-cells share/ many similarities to pancreatic β-cells, including the peptidases required for proinsulin processing, hormone storage and a glucosestimulated hormone secretion mechanism. In the present study, we demonstrate that not only K-cells, but also L-cells engineered with the human preproinsulin gene are able to synthesize, store and, upon glucose stimulation, release mature insulin. When the mouse enteroendocrine STC-1 cell line was transfected with the human preproinsulin gene, driven either by the K-cell specific GIP promoter or by the constitutive cytomegalovirus (CMV) promoter, human insulin co-localizes in vesicles that contain GIP (GIP or CMV promoter) or GLP-1 (CMV promoter). Exposure to glucose of engineered STC-1 cells led to a marked insulin secretion, which was 7-fold greater when the insulin gene was driven by the CMV promoter (expressed both in K-cells and L-cells) than when it was driven by the GIP promoter (expressed only in K-cells). Thus, besides pancreatic β-cells, both gastrointestinal enteroendocrine K-cells and L-cells can be selected as the target cell in a gene therapy strategy to treat patients with type 1 diabetes mellitus.

Perez E.G.,Millennium Institute for Cell Dynamics and Biotechnology | Perez E.G.,University of Santiago de Chile | Mendez-Galvez C.,University of Chile | Cassels B.K.,Millennium Institute for Cell Dynamics and Biotechnology | Cassels B.K.,University of Chile
Natural Product Reports | Year: 2012

This review covers classical and modern structural modifications of the alkaloid, the more recent (since 2007) syntheses of cytisine and analogues, and the pharmacology of these compounds, with emphasis on their interactions with nicotinic receptors. 89 references are cited. © The Royal Society of Chemistry 2012.

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